This R01, submitted in response to RFA-DA-09-001 (Medications Development for Cannabis-Related Disorders), has been modified to accommodate a 2-year budget. The grant proposes using pre-clinical measures of cannabinoid withdrawal in non-human primates to identify potential pharmacotherapies of marijuana dependence. Over one-half of daily marijuana users experience withdrawal upon discontinuation of use, which is reported to drive marijuana smoking. Pharmacotherapy of marijuana withdrawal is associated with decreased relapse to marijuana use in the clinical laboratory and, therefore, is a viable strategy for promoting abstinence. This application addresses a compelling need for pre-clinical assays that can provide rapid and efficient testing of drugs for their capacity to attenuate cannabinoid withdrawal. The cannabinoid antagonist rimonabant will provide an index of withdrawal in rhesus monkeys receiving chronic treatment with [unreadable]9-tetrahydrocannabinol, the cannabinoid primarily responsible for the abuse and dependence liability of marijuana. Discriminative stimulus effects will provide a measure of the private experience of withdrawal. Medications will be examined for their ability to modify not only discriminative stimulus effects but also other signs of withdrawal including head shaking and increased night activity in the home cage (i.e. sleep disruption). Aim 1 will examine modification of cannabinoid withdrawal by [unreadable]9-tetrahydrocannabionol alone and in combination with [unreadable]2-adrenergic agonists (clonidine and lofexidine). The combination has been reported to attenuate marijuana withdrawal more effectively than either drug alone. Quantitative pharmacologic (i.e. isobolographic) analysis will be used to examine whether attenuation of cannabinoid withdrawal by the drug combination is additive, less than additive, or greater than additive (synergistic). Synergistic drug combinations could be especially effective therapeutics. Aim 2 evaluates pharmacotherapy of sleep disruption as a strategy for attenuating cannabinoid withdrawal indexed by discriminative stimulus effects and head shaking during the day. Drugs to be studied for their capacity to attenuate sleep disruption as well as next-day expression of cannabinoid withdrawal signs will include a benzodiazepine (zolpidem or Ambien(), the 5HT2A antagonist M100907, and the melatonin agonist ramelteon (Rozerem(). Collectively, these specific aims provide a framework for developing novel pharmacotherapies of marijuana withdrawal that could markedly decrease marijuana use and dependence.